5-pyrazolylthiopropionic acid derivatives

ABSTRACT

1,3-Disubstituted-5,6-dihydrothiopyrano(2,3-c) pyrazoles are synthesized from the new 3-((1,3-disubstituted-5pyrazolyl)thio)propionic acids described. The new fused-ring compounds have excellent anti-inflammatory activity; they relieve edemas and are also useful as antipyretics and analgesics.

United States Patent Swett et al.

[ 51 May 23, 1972 [54] S-PYRAZOLYLTHIOPROPIONIC ACID DERIVATIVES [72]Inventors: Leo Ralph Swett; James Daniel Ratalczyk,

both of Waukegan, Ill.

52 U.S.Cl. ..260/310R 51 Int. Cl. .C07d49/18 [58] Field of Search..260/3 10 R [56] References Cited UNITED STATES PATENTS 3,282,95411/1966 Stein et a]. ..260/310 R OTHER PUBLICATIONS Pain, J. Chem. Soc.(London), 1963, Pages 1332- 1333, QD1.C6.

Primary ExaminerNatalie Trousof Att0mey-Robert L. Niblack A138! RACT l,3-Disubstituted-5,6-dihydrothiopyrano[2,3-c] pyrazoles are synthesizedfrom the new 3-[( l ,3-disubstituted-5- pyrazolyl)thio]propionic acidsdescribed. The new fused-ring compounds have excellent anti-inflammatoryactivity; they relieve edemas and are also useful as antipyretics andanalgesics.

4 Claims, No Drawings S-PYRAZOLYLTHIOPROPIONIC ACID DERIVATIVES Thisapplication is a division of application Ser. No. 717,913, filed Apr. 1,1968, now US. Pat. No. 3,590,048.

The present invention is directed to compounds of the formula wherein Ris methyl or phenyl, R is hydrogen or methyl, and Y is oxygen or OHwherein R and R have the above-identified meaning, which are used inthis process.

In a general embodiment, the above intermediates are made from thecorresponding 1-substituted-3-methyl-2-pyrazoline- 5-thione which inturn is made from the corresponding 5- pyrazolone with phosphorouspentasulfide. The pyrazoline-S- thione is then reacted with3-bromopropionic acid or 3- bromobutyric acid. Ring closure of thesepyrazolylthiopropionic acid derivatives with polyphosphoric acidproduces the compounds of formula I wherein Y is oxygen. Reduction ofthese ketones with lithium aluminum hydride produces the compounds offormula l wherein Y is The new compounds exhibit anti-inflammatory andantipyretic activity when administered to warm-blooded animals at oraldosages of 25-100 mg/kg; at oral dosages above 100 mg/kg the newcompounds also show analgesic effects and reduce capillary permeability.The compounds of formula I wherein Y is oxygen are generally moreeffective, i.e., their effective dosage level is lower than thatestablished for the compounds of formula I wherein Y is H The newcompounds are particularly interesting as anti-inflammatories andanti-pyretics because their therapeutic index is very high (thecompounds of formula I have oral toxicities between 900 and 2,000mg/kg), and because they exhibit their activity at low oral dosages.

The following examples are given as illustrations for the preparationsof the new intermediates of formula II and the anti-inflammatorycompounds of formula 1. However, these examples are not intended tolimit the invention in any respect. In all examples, the analyticalvalues are found to be in good agreement with the compounds of theassigned structure.

EXAMPLE 1 l, 3-Dimethyl-2-pyrazoline-5-thione To a stirred solution of 112.1 g. of 1,3-dimethyl-2- pyrazolin-S-one in 1,500 ml. of refluxingxylene is added 87 g. of phosphorous pentasulfide. The resulting mixtureis stirred another 45 minutes under reflux and then allowed to settle.The hot xylene layer is decanted from the formed sludge and concentratedunder reduced pressure. The obtained residue from the xylene concentrateis crystallized from a minimum amount of hot isopropyl alcohol,resulting in 11.0 g. of pure 1,3-dimethyl-2-pyrazoline-5-thione, meltingat 133.5134.5 C.

EXAMPLE 2 3-[( l,3-Dimethyl-5-pyrazolyl)thio]propi0nic acid To asolution of 15.1 g. of sodium bicarbonate in 300 ml. of water is added20.5 g. of 1,3-dimethyl-2-pyrazoline-5-thione and the mixture is heatedwith stirring to C. A solution of 24.5 g. of 3-bromopropionic acid in300 ml. of water containing 13.5 g. of sodium bicarbonate is then addedat once to the above hot mixtures and stirring is continued at 70 C. for3 hours. Filtration of the hot solution removes a small amount ofinsoluble material. The filtrate is chilled and acidified with glacialacetic acid to give 26.7 g. (84 percent of theory) of pure3-[(1,3-dimethyl-5-pyrazolyl)thio] propionic acid, melting at 127128 C.

EXAMPLE 3 5,6-Dihydrol ,3-dimethylthiopyrano[2,3c]pyrazol-4( 1H one Amixture of 20 g. of 3-[(l,3-dimethyl-5-pyrazoyl)thio]- propionic acidand 250 g. of polyphosphoric acid is heated for 1 hour to C. andsubsequently poured into crushed ice. The resulting clear solution isneutralized with a 50 percent aqueous sodium hydroxide solution whilebeing chilled in an ice bath. The crude ketone is crystallized fromwater with charcoal treatment to produce 12.9 g. (71 percent of theory)of pure, colorless needles of 5,6-dihydro-l,3- dimethylthiopyrano[2,3-c]pyrazol-4(1H)-one, melting at l l3l 14 C.

EXAMPLE 4 1,4,5,6-Tetrahydro-1,3-dimethylthiopyrano[2,3-c1pyrazol- 4-01To a suspension of 1.2 g. of lithium aluminum hydride in 250 m1. ofanhydrous ether is added, portionwise, 4.5 g. of 5,6- dihydrol,3-dimethylthiopyrano[2,3-c]pyrazol4( 1H )one and the mixture isrefluxed for 4 hours. Subsequently, the excess lithium aluminum hydrideis decomposed by the addition of 1.1 ml. of water, and a solution of 1.1ml. of 15% aqueous sodium hydride and 3.3 ml. of water is added beforethe mixture is filtered. The filtrate is evaporated to dryness underreduced pressure and the residue is crystallized by dissolving it in theminimum amount of benzene and inducing crystallization by the additionof hexane to give 3.7 g. of 1,4,5,6- tetrahydro- 1,3-dimethylthiopyrano[ 2,3-c]pyrazol-4-ol, melting at 95-96 C.

EXAMPLE 5 3-[( l,3-Dimethyl-5-pyrazolyl)thiolbutyric acid Following theprocedure of Example 2 but replacing the 3- bromopropionic acid usedthere with an equivalent amount of 3-bromobutyric acid produces 3-[( l,3-dimethyl-5- pyrazolyl)thio]butyric acid. The pure material isobtained in a yield of 61 percent of theory as a yellow oil boiling at-18 0 C. under 1-4 mm pressure.

EXAMPLE 6 5,6-Dihydro-1 ,3,6-trimethylthiopyrano[2,3c]pyrazol-4( lH)-one By following the procedure of Example 3 with the compound ofExample 5, 5,6-dihydro-l,3,6-trimethylthiopyrano[ 2,3c]4( 1H)-one isobtained in a yield of53.3 percent of theory after crystallizing thecrude product from water. The pure compound melts at 101.5 102.5 C.

EXAMPLE 7 1,4,5 ,-Tetrahydro- 1 ,3 ,6-trimethylthiopyrano 2,3-clpyrazol-4-ol By reducing 6.9 g. of the compound of Example 6 by themethod of Example 4 using 1.5 g. of lithium aluminum hydride, a mixtureof the cis and trans isomers of l,4,5,6- tetrahydrol ,3,6-trimethylthiopyrano[ 2, 3-c]pyrazo1-4-ol is obtained in a yield of2.4 g. The mixture has an indefinite melting point but analysis and theinfrared spectrum confirm the structure of the desired compound.

EXAMPLE 8 3-[( 3-Methyll -phenyl-pyrazo1yl)thio]propionic acid3-Methyl-1-phenyl-2-pyrazoline-5-thione is made from 3-methyl-l-phenyl-2-pyrazolin-5-one and phosphorous pentasulfide inaccordance with the process of Example 1. The pure compound,crystallized from ethanol, melts at 1 1 12 C.

By following the procedure of Example 2 using 35.7 g. of the abovethione and 29.0 g. of 3-bromopropionic acid, 3-]( 3-methyl-l-phenyl-5-pyrazolyl)thiolpropionic acid is obtained in a yieldof 38.4 g. after crystallizing the crude material fromethylacetate/hexane; it melts at l05-l07 C.

EXAMPLE 9 5 ,6-Dihydro-3-methyll-phenylthiopyrano[ 2,3c]pyrazol-4lH)-one Following the procedure of Example 3 with 92.0 g. of thematerial of Example 8 and 1,565 g. of polyphosphoric acid, crude 5,6-dihydro-3-methyll -phenylthiopyrano[ 2,3- c]pyrazol4( lH)-one isobtained which, after crystallization from aqueous ethanol, weighs 74.0g.; it melts at 124.5-l26.5 C.

EXAMPLE l0 1,4,5 ,6-Tetrahydro-3-methyl- 1 -phenylthiopyrano[ 2,3-c]pyrazol-4-ol The compound of Example 9 is reduced in accordance withthe procedure of Example 4 to produce l,4,5,6-tetrahydro-3-methyl-l-phenylthiopyrano[2,3c]pyrazol-4ol in a yield of 83percent oftheory after crystallizing the crude material from benzene/hexane. Thepure material melts at 144145 C.

EXAMPLE 1 l The anti-edema effect of the above compounds is establishedby the following procedure: edema is produced in the paws of rats by theinjection of carrageenan according to the method described by Winter etal (Proc., Soc., Exp. BioL, Med., 1962, volume 1 l l, page 544). Thetest compounds are administered orally at various dosages (6-rates perdosage) 30 minutes prior to the administration of the edema-producingcarrageenan. Edema is expressed as percent increase over normal pawsize; edema inhibition is calculated from the difference between theaverage edema size of the control group and the average edema size ofthe test group. The ED (i.e., the dose required to produce 25 percentedema size reduction) is determined from a dosage/effect curve drawn onlogarithmic graph paper. In this manner, the ED of the compound of thecompound of Example 6 is established to be 49 mg/kg orally; the ED ofthe compound of Example 3 is determined to be 60 mg/kg orally. With thecompounds of Example 4, percent edema size reduction 2 found at 100mg/kg orally.

EXAMPLE 1 2 4-6 rats er roup.

The E 50 %50 percent reduction of fever) for the compound of Example 6is found to be at 50 mg/kg orally; with the compound of Example 3, a 15percent reduction of fever is found at 50 mg/kg orally.

EXAMPLE l3 Analgesic and reduction of capillary permeability producedwith the compounds of the present invention is established by amodification of the method described by Whittle (Brit. J. Phann, 1964,volume 22, page 246): Mice are pre-treated with the test compound or aplacebo by oral administration thereof. Twenty minutes later, the miceare injected intravenously with mg/kg of a 1 percent Evans Blue solutionin isotonic saline followed in 10 minutes by an intraperitonealinjection of 0.4 ml. of 0.5 percent aqueous acetic acid. writhingproduced by the acid is counted for a period of 20 minutes. Analgesiceffect is the present inhibition of writhes calculated from thedifference between the control group and the test group. Inhibition ofpermeability is calculated as the present inhibition of dye leakage intothe peritoneal cavity. Each group of test and control animals comprises5 mice.

The analgesic ED for the compound of Example 6, established in thismanner, is mg/kg orally and the ED for capillary permeability(calculated dose which inhibits 50 percent dye leakage) is found to beat 220 mg/kg orally; the analgesic ED of the compound of Example 3 ismg/kg orally and the capillary permeability is found to be mg/kg orally.

The process of making the compounds of formula 1 from the newintermediates of formula 11 requires no solvent and is simply carriedout by treating the intermediate with an at least about lO-fold excessby weight of polyphosphoric acid. Excellent results are obtained byusing a lO- to l2-fold excess of polyphosphoric acid based on the weightof the intermediate but no undue effect is apparent if a 20-fold excessof polyphosphoric acid is used. The two reactants are heated for atleast 30 minutes to a temperature of between 100 and 160 C. Heatingbeyond 3 hours serves no beneficial purpose and temperatures above 160C. should be avoided in order to reduce possible by-product formation.

We claim:

1. A compound of the formula R wherein R is methyl or phenyl and R ishydrogen or methyl. 2. The compound of claim 1 wherein R and R both aremethyl.

3. The compound of claim 1 wherein R is phenyl and R is hydrogen.

4. The compound of claim 1 wherein R is methyl and R is hydrogen.

2. The compound of claim 1 wherein R and R'' both are methyl.
 3. Thecompound of claim 1 wherein R is phenyl and R'' is hydrogen.
 4. Thecompound of claim 1 wherein R is methyl and R'' is hydrogen.